A 57-year-old male, with a history of bladder and prostate cancer, and pancreatitis, presents with dark urine and clay-colored floating stools. Labs were notable for white blood cell count 5900, lipase 449, alkaline phosphatase 731, total bilirubin 6.3, AST 381, and ALT 991. CA 19-9 was elevated at 184 and CEA was less than 1. Serum IgG4 level was within normal limit. MRI showed worsening left lateral intrahepatic biliary ductal dilatation with abrupt cutoff at a stellate focus of enhancement, raising concern for cholangiocarcinoma. He underwent endoscopic retrograde cholangio-pancreatography (ERCP), which showed localized stricture of the left main hepatic duct. A bile duct brushing revealed atypical ductal epithelial cells. The patient elected for a left lateral liver segmentectomy. The following sections resulted from the liver segmentectomy (Figures 1-4).

The histopathologic features of IgG4-related disease (IgG4-RD) were first described in 2001 by Hamano et al (1) for sclerosing pancreatitis (type I autoimmune pancreatitis). Later discoveries of similar diseases in other organs, including the biliary system, led to the recognition of IgG4-related disease as a systemic immune-mediated disease (2). The consensus criteria for histopathologic diagnosis of IgG4-RD requires two or more of the following characteristic features (3):

a dense lymphoplasmacytic infiltrate,

storiform fibrosis,

obliterative phlebitis (Figure 5),

increased IgG4+ plasma cells/HPF (Figure 6), and

IgG4+/IgG+ plasma cell ratio of >40%.

However, definitive diagnosis of IgG4-RD requires correlation with clinical features. Therefore, it is recommended to classify cases into one of three categories (3):

histologically highly suggestive of IgG4-RD,

probable histologic features of IgG4-RD, and

insufficient histopathologic evidence of IgG4-RD.

The first category (highly suggestive of IgG4-RD) requires the presence of either storiform fibrosis or obliterative phlebitis, together with an elevated absolute and relative IgG4+ plasma cell count.

The second category (probable histologic features of IgG4-RD) typically lacks some of the histopathologic features of IgG4-RD but shows an elevated IgG4+ plasma cell count. These cases require correlation with clinical and radiologic findings, including serum IgG4 levels, and investigation for other organ involvement. A caveat is that up to half of the patients with IgG4-RD have normal serum IgG44, as in this case.

The third category of ‘insufficient histopathologic evidence of IgG4-RD’ includes cases not meeting criteria for the above first two categories. However, this category does not exclude the possibility of IgG4-RD.

IgG4-related sclerosing cholangitis (IgG4-RSC) often presents with obstructive jaundice, elevated liver enzymes, and imaging findings of biliary stricture or mass (5-6). IgG4-RSC is often associated with autoimmune pancreatitis, as in this patient. Intrahepatic bile duct involvement is characterized by a portal mixed inflammatory infiltrate with lymphocytes, increased IgG4+ plasma cells (Figure 6 and 1-3), eosinophils, and a variable amount of fibrosis (Figure 4). Obliterative phlebitis is also present in this patient (Figure 5).

The exact pathophysiology of IgG4-RD is not clear. However, aberrant T- cell regulation was suggested to be the underlying mechanism. Follicular helper T cells and regulatory T cells are thought to play an essential role in IgG4-RD, specifically in the class switching of B cells (7). Interestingly, it is hypothesized that the increased IgG4+ plasma cells may be secondary to cytokine production rather than being pathogenic. A recent study identified Annexin A11 as a potential auto-antigen involved in the pathogenesis of autoimmune pancreatitis (8).

Treatment decisions are based on clinical presentation, organ involvement, and risk of recurrence, but treatment is not always necessary, especially in asymptomatic patients. However, treatment is recommended in patients with vital organ involvement, such as pancreatobiliary organs, kidneys, and the central nervous system. Most patients respond to steroid therapy regardless of organ involvement and clinical presentation. In relapsed IgG4-RD patients, other immunosuppressive medications have been used to maintain disease remission and decrease the side effects of steroids. Of note, this patient responded well to steroid and CellCept therapy and is currently in clinical remission.

Other answer choices:

Inflammatory myofibroblastic tumor (IMT) also has an intense lymphoplasmacytic infiltration, sometimes storiform fibrosis and obliterative phlebitis. However, the stromal cells in IMT are often very prominent with cytologic atypia, which is not seen in this case. Most IMTs are positive for ALK1 and ROS1 expression, while IgG4-RSC is negative for both markers.

Infectious cholangitis, including bacterial, mycobacterial, viral, and spirochetal, can also mimic IgG4-RSC. However, infectious cholangitis usually does not present with significantly increased IgG4+ plasma cells or other histologic features of IgG4-RSC, and serum IgG4 is often not elevated. Suggestive histologic features, such as granulomas seen in mycobacterial infection, IHC or special stains may be helpful to point to a specific infectious pathogen.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that involves small intrahepatic bile ducts and most commonly seen in middle aged women. Histologically, the characteristic features are portal granulomatous inflammation with bile duct damage and cholestatic reaction. Most patients have a positive anti-mitochondrial antibody. Portal tracts infiltrated by plasma cells are rare, and there is no significant increase in IgG4+ plasma cells.

IgG4-related sclerosing cholangitis (Correct Answer)

Primary sclerosing cholangitis (PSC) is another entity that can closely mimic IgG4-RSC both clinically and histologically. The distinction between the two can be very difficult at times. However, PSC has a strong association with ulcerative colitis. ERCP is the gold standard for diagnosis of sclerosing cholangitic diseases. The cholangiogram for PSC often shows beading, whereas IgG4-RSC often has long strictures involving hilar structures, including extrahepatic bile ducts and the lower common bile duct, which was seen in this case. Cholangiography for IgG4-RSC has specificity of 88% but sensitivity of 45% (9). Histologically, PSC often has patchy lymphocytic injury of bile ducts with concentric fibrosis around bile ducts- so called “onion-skin” like fibrosis. The bile duct caliber is often out of proportion to accompanying vasculature and there is degeneration of duct epithelium, also known as fibro-obliterative lesions. In contrast, expansile and circumscribed portal fibroinflammatory nodules favor IgG4-RSC, in addition to significantly increased IgG4+ plasma cells and elevated serum IgG4 level. In addition, more often than not, IgG4-RSC is associated with autoimmune pancreatitis and responds to steroid therapy.